TY - JOUR TI - Structure and functional properties of Norrin mimic Wnt for signalling with Frizzled4, Lrp5/6, and proteoglycan AU - Chang, Tao-Hsin AU - Hsieh, Fu-Lien AU - Zebisch, Matthias AU - Harlos, Karl AU - Elegheert, Jonathan AU - Jones, E Yvonne A2 - Kuriyan, John VL - 4 PY - 2015 DA - 2015/07/09 SP - e06554 C1 - eLife 2015;4:e06554 DO - 10.7554/eLife.06554 UR - https://doi.org/10.7554/eLife.06554 AB - Wnt signalling regulates multiple processes including angiogenesis, inflammation, and tumorigenesis. Norrin (Norrie Disease Protein) is a cystine-knot like growth factor. Although unrelated to Wnt, Norrin activates the Wnt/β-catenin pathway. Signal complex formation involves Frizzled4 (Fz4), low-density lipoprotein receptor related protein 5/6 (Lrp5/6), Tetraspanin-12 and glycosaminoglycans (GAGs). Here, we report crystallographic and small-angle X-ray scattering analyses of Norrin in complex with Fz4 cysteine-rich domain (Fz4CRD), of this complex bound with GAG analogues, and of unliganded Norrin and Fz4CRD. Our structural, biophysical and cellular data, map Fz4 and putative Lrp5/6 binding sites to distinct patches on Norrin, and reveal a GAG binding site spanning Norrin and Fz4CRD. These results explain numerous disease-associated mutations. Comparison with the Xenopus Wnt8–mouse Fz8CRD complex reveals Norrin mimics Wnt for Frizzled recognition. The production and characterization of wild-type and mutant Norrins reported here open new avenues for the development of therapeutics to combat abnormal Norrin/Wnt signalling. KW - Wnt signalling KW - cystine-knot growth factor KW - retinal disease KW - angiogenesis KW - crystal structure KW - blood brain barrier JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -